Skip to main content

Advertisement

SpringerLink
Log in

Pharmacological and Host Considerations Surrounding Dose Selection and Duration of Therapy with Echinocandins

  • Pharmacology and Pharmacodynamics of Antifungal Agents (ME Klepser, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Caspofungin, micafungin and anidulafungin are antifungal drugs with excellent safety profiles. Dosing regimens and treatment durations must be appropriate for optimal patient outcomes. Overall, factors that affect dosing of all three drugs are similar. Drug-specific properties, including in vitro concentration-dependent antifungal activity, activity against fungal biofilms, and pharmacokinetic and pharmacodynamic parameters influence dose selection and duration of therapy. Dosing strategies that provide “unbound” plasma drug concentrations exceeding the minimum inhibitory concentration (or minimum effective concentration) of the fungus are essential. Patient weight, age and illness severity are also important considerations for adequate exposure to drug: individuals >66 kg, pediatric patients and the critically-ill clear drug at higher rates although drug product information guidelines do not recommend for these populations to receive doses higher than those currently used. Clinical studies of treatment of, and prophylaxis against, Candida and Aspergillus infection indicate that currently recommended dosing regimens are adequate in most instances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50(8):1091–100.

    Article  PubMed  Google Scholar 

  2. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12(3):220–9.

    Article  PubMed  CAS  Google Scholar 

  3. Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48(3):265–73.

    Article  PubMed  CAS  Google Scholar 

  4. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11.

    Article  PubMed  Google Scholar 

  5. •• Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards Jr JE, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35. This article is the most recent update of the IDSA clinical practice guidelines for managing candidiasis. It addresses use of different antifungals including the echinocandins in the management of a variety of Candida infections with recommendations for dose and duration of therapy.

    Article  PubMed  CAS  Google Scholar 

  6. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327–60.

    Article  PubMed  CAS  Google Scholar 

  7. Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J Med Vet Mycol. 1997;35(2):79–86.

    Article  PubMed  CAS  Google Scholar 

  8. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008;46(1):150–6.

    Article  PubMed  CAS  Google Scholar 

  9. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance. J Clin Microbiol. 2006;44(3):760–3.

    Article  PubMed  CAS  Google Scholar 

  10. Antachopoulos C, Meletiadis J, Sein T, Roilides E, Walsh TJ. Comparative in vitro pharmacodynamics of caspofungin, micafungin, and anidulafungin against germinated and non-germinated Aspergillus conidia. Antimicrob Agents Chemother. 2008;52(1):321–8.

    Article  PubMed  CAS  Google Scholar 

  11. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, et al. In vitro susceptibility of clinical isolates of Aspergillus spp. to anidulafungin, caspofungin, and micafungin: a head-to-head comparison using the CLSI M38-A2 broth microdilution method. J Clin Microbiol. 2009;47(10):3323–5.

    Article  PubMed  CAS  Google Scholar 

  12. Bal AM. The echinocandins: three useful choices or three too many? Int J Antimicrob Agents. 2010;35(1):13–8.

    Article  PubMed  CAS  Google Scholar 

  13. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142–51.

    Article  PubMed  CAS  Google Scholar 

  14. Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev Iberoam Micol. 2003;20(4):121–36.

    PubMed  Google Scholar 

  15. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, et al. Wild-type MIC distributions and epidemiological cutoff values for the echinocandins and Candida spp. J Clin Microbiol. 2010;48(1):52–6.

    Article  PubMed  CAS  Google Scholar 

  16. Messer SA, Diekema DJ, Boyken L, Tendolkar S, Hollis RJ, Pfaller MA. Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp. J Clin Microbiol. 2006;44(2):324–6.

    Article  PubMed  CAS  Google Scholar 

  17. •• Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, et al. Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat. 2011;14(3):164–76. An important study proposing species-specific clinical breakpoints for Candida and the echinocandins are better than MICs in detecting emerging resistance and in predicting risk for clinical failure.

    Article  PubMed  CAS  Google Scholar 

  18. Perlin DS. Resistance to echinocandin-class antifungal drugs. Drug Resist Updat. 2007;10(3):121–30.

    Article  PubMed  CAS  Google Scholar 

  19. •• Pfaller M, Boyken L, Hollis R, Kroeger J, Messer S, Tendolkar S, et al. Use of epidemiological cutoff values to examine 9-year trends in susceptibility of Candida species to anidulafungin, caspofungin, and micafungin. J Clin Microbiol. 2011;49(2):624–9. This study is pivotal in establishing epidemiological cut off values for determining resistance trends among the three echinocandins and Candida spp.

    Article  PubMed  CAS  Google Scholar 

  20. •• Espinel-Ingroff A, Fothergill A, Fuller J, Johnson E, Pelaez T, Turnidge J. Wild-type MIC distributions and epidemiological cutoff values for caspofungin and Aspergillus spp. for the CLSI broth microdilution method (M38-A2 document). Antimicrob Agents Chemother. 2011;55(6):2855–9. The only study in establishing epidemiological cut off values for caspofungin and Aspergillus spp.

    Article  PubMed  CAS  Google Scholar 

  21. • Cateau E, Berjeaud JM, Imbert C. Possible role of azole and echinocandin lock solutions in the control of Candida biofilms associated with silicone. Int J Antimicrob Agents. 2011;37(4):380–4. This study demonstrates that echinocandin lock therapy had significant inhibitory effects against Candida biofilms in situ, enhancing the management of candidiasis in patients with indwelling catheters.

    Article  PubMed  CAS  Google Scholar 

  22. Cateau E, Rodier MH, Imbert C. In vitro efficacies of caspofungin or micafungin catheter lock solutions on Candida albicans biofilm growth. J Antimicrob Chemother. 2008;62(1):153–5.

    Article  PubMed  CAS  Google Scholar 

  23. Chatzimoschou A, Katragkou A, Simitsopoulou M, Antachopoulos C, Georgiadou E, Walsh TJ, et al. Activities of triazole-echinocandin combinations against Candida species in biofilms and as planktonic cells. Antimicrob Agents Chemother. 2011;55(5):1968–74.

    Article  PubMed  CAS  Google Scholar 

  24. Fiori B, Posteraro B, Torelli R, Tumbarello M, Perlin DS, Fadda G, et al. In vitro activities of anidulafungin and other antifungal agents against biofilms formed by clinical isolates of different Candida and Aspergillus species. Antimicrob Agents Chemother. 2011;55(6):3031–5.

    Article  PubMed  CAS  Google Scholar 

  25. Kucharikova S, Tournu H, Holtappels M, Van Dijck P, Lagrou K. In vivo efficacy of anidulafungin against mature Candida albicans biofilms in a novel rat model of catheter-associated Candidiasis. Antimicrob Agents Chemother. 2010;54(10):4474–5.

    Article  PubMed  CAS  Google Scholar 

  26. Shuford JA, Rouse MS, Piper KE, Steckelberg JM, Patel R. Evaluation of caspofungin and amphotericin B deoxycholate against Candida albicans biofilms in an experimental intravascular catheter infection model. J Infect Dis. 2006;194(5):710–3.

    Article  PubMed  CAS  Google Scholar 

  27. Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805–17.

    Article  PubMed  CAS  Google Scholar 

  28. Hiemenz J, Cagnoni P, Simpson D, Devine S, Chao N, Keirns J, et al. Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant. Antimicrob Agents Chemother. 2005;49(4):1331–6.

    Article  PubMed  CAS  Google Scholar 

  29. Stone JA, Holland SD, Wickersham PJ, Sterrett A, Schwartz M, Bonfiglio C, et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother. 2002;46(3):739–45.

    Article  PubMed  CAS  Google Scholar 

  30. Tabata K, Katashima M, Kawamura A, Kagayama A, Kohno S. Pharmacokinetics-pharmacodynamics of micafungin in Japanese patients with deep-seated mycosis. Eur J Drug Metab Pharmacokinet. 2006;31(2):123–8.

    Article  PubMed  CAS  Google Scholar 

  31. Migoya EM, Mistry GC, Stone JA, Comisar W, Sun P, Norcross A, et al. Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants. J Clin Pharmacol. 2011;51(2):202–11.

    Article  PubMed  CAS  Google Scholar 

  32. Thye D, Shepherd B, White RJ, et al. Anidulafungin: a phase 1 study to identify the maximum tolerated dose in healthy volunteers [poster 36]. Presented at 41st Interscience Conference on Antimicrobial Agents. Chicago, United States; December, 2001.

  33. Mycamine® (micafungin sodium). Prescribing information. Astellas Pharma, Deerfield, IL, 2011.

  34. Damle B, Stogniew M, Dowell J. Pharmacokinetics and tissue distribution of anidulafungin in rats. Antimicrob Agents Chemother. 2008;52(7):2673–6.

    Article  PubMed  CAS  Google Scholar 

  35. Hebert MF, Smith HE, Marbury TC, Swan SK, Smith WB, Townsend RW, et al. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol. 2005;45(10):1145–52.

    Article  PubMed  CAS  Google Scholar 

  36. Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM, et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother. 2004;48(3):815–23.

    Article  PubMed  CAS  Google Scholar 

  37. •• Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54(6):2497–506. An important in vivo pharmacodynamic study demonstrating the relationships between echinocandins doses and efficacy against different Candida spp.

    Article  PubMed  CAS  Google Scholar 

  38. Crandon JL, Banevicius MA, Fang AF, Crownover PH, Knauft RF, Pope JS, et al. Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults. Antimicrob Agents Chemother. 2009;53(12):5102–7.

    Article  PubMed  CAS  Google Scholar 

  39. Walsh TJ, Goutelle S, Jelliffe RW, Golden JA, Little EA, DeVoe C, et al. Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients. Antimicrob Agents Chemother. 2010;54(8):3451–9.

    Article  PubMed  CAS  Google Scholar 

  40. Yamada N, Kumada K, Kishino S, Mochizuki N, Ohno K, Ogura S. Distribution of micafungin in the tissue fluids of patients with invasive fungal infections. J Infect Chemother. 2011;17(5):731–4.

    Article  PubMed  CAS  Google Scholar 

  41. Damle BD, Dowell JA, Walsky RL, Weber GL, Stogniew M, Inskeep PB. In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin. Antimicrob Agents Chemother. 2009;53(3):1149–56.

    Article  PubMed  CAS  Google Scholar 

  42. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs. 2011;71(1):11–41.

    Article  PubMed  CAS  Google Scholar 

  43. Cancidas™ (caspofungin acetate). Prescribing information. Merck, Sharp and Dohme, Whitehouse Station, NJ, 2010.

  44. Mistry GC, Migoya E, Deutsch PJ, Winchell G, Hesney M, Li S, et al. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations. J Clin Pharmacol. 2007;47(8):951–61.

    Article  PubMed  CAS  Google Scholar 

  45. Spriet I, Meersseman W, Annaert P, de Hoon J, Willems L. Pharmacokinetics of caspofungin in a critically ill patient with liver cirrhosis. Eur J Clin Pharmacol. 2011;67(7):753–5.

    Article  PubMed  Google Scholar 

  46. Eraxis™ (anidulafungin). Prescribing information. Pfizer, New York, 2010.

  47. Dowell JA, Stogniew M, Krause D, Damle B. Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment. J Clin Pharmacol. 2007;47(4):461–70.

    Article  PubMed  CAS  Google Scholar 

  48. Leitner JM, Meyer B, Fuhrmann V, Saria K, Zuba C, Jager W, et al. Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration. J Antimicrob Chemother. 2011;66(4):880–4.

    Article  PubMed  CAS  Google Scholar 

  49. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49(11):4536–45.

    Article  PubMed  CAS  Google Scholar 

  50. Neely M, Jafri HS, Seibel N, Knapp K, Adamson PC, Bradshaw SK, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009;53(4):1450–6.

    Article  PubMed  CAS  Google Scholar 

  51. Saez-Llorens X, Macias M, Maiya P, Pineros J, Jafri HS, Chatterjee A, et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother. 2009;53(3):869–75.

    Article  PubMed  CAS  Google Scholar 

  52. Li CC, Sun P, Dong Y, Bi S, Desai R, Dockendorf MF, et al. Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients. Antimicrob Agents Chemother. 2011;55(5):2098–105.

    Article  PubMed  CAS  Google Scholar 

  53. Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E, et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005;49(8):3317–24.

    Article  PubMed  CAS  Google Scholar 

  54. Benjamin Jr DK, Smith PB, Arrieta A, Castro L, Sanchez PJ, Kaufman D, et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharmacol Ther. 2010;87(1):93–9.

    Article  PubMed  CAS  Google Scholar 

  55. Heresi GP, Gerstmann DR, Reed MD, van den Anker JN, Blumer JL, Kovanda L, et al. The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants. Pediatr Infect Dis J. 2006;25(12):1110–5.

    Article  PubMed  Google Scholar 

  56. Kawada M, Fukuoka N, Kondo M, Okazaki K, Kusaka T, Kawada K, et al. Pharmacokinetics of prophylactic micafungin in very-low-birth-weight infants. Pediatr Infect Dis J. 2009;28(9):840–2.

    Article  PubMed  Google Scholar 

  57. • Mehta PA, Vinks AA, Filipovich A, Bleesing J, Jodele S, Jordan MB, et al. Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant. 2010;16(10):1458–62. This study provides data indicating that alternate day micafungin at 3 mg/kg was well tolerated in HSCT pediatric patients and provided blood levels above the MIC of most fungal pathogens.

    Article  PubMed  Google Scholar 

  58. Smith PB, Walsh TJ, Hope W, Arrieta A, Takada A, Kovanda LL, et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr Infect Dis J. 2009;28(5):412–5.

    Article  PubMed  Google Scholar 

  59. Ascher S, Smith PB, Benjamin Jr DK. Safety of micafungin in infants: insights into optimal dosing. Expert Opin Drug Saf. 2011;10(2):281–6.

    Article  PubMed  CAS  Google Scholar 

  60. Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007;51(10):3714–9.

    Article  PubMed  CAS  Google Scholar 

  61. Hope WW, Smith PB, Arrieta A, Buell DN, Roy M, Kaibara A, et al. Population pharmacokinetics of micafungin in neonates and young infants. Antimicrob Agents Chemother. 2010;54(6):2633–7.

    Article  PubMed  CAS  Google Scholar 

  62. Cohen-Wolkowiez M, Benjamin Jr DK, Piper L, Cheifetz IM, Moran C, Liu P, et al. Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates. Clin Pharmacol Ther. 2011;89(5):702–7.

    Article  PubMed  CAS  Google Scholar 

  63. • Cornely OA, Vehreschild JJ, Vehreschild MJ, Wurthwein G, Arenz D, Schwartz S, et al. Phase II dose escalation study of caspofungin for invasive Aspergillosis. Antimicrob Agents Chemother. 2011;55(12):5798–803. Caspofungin doses of 200 mg/day were well tolerated in first-line treatment of IA.

    Article  PubMed  CAS  Google Scholar 

  64. Dowell JA, Knebel W, Ludden T, Stogniew M, Krause D, Henkel T. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol. 2004;44(6):590–8.

    Article  PubMed  CAS  Google Scholar 

  65. Nguyen TH, Hoppe-Tichy T, Geiss HK, Rastall AC, Swoboda S, Schmidt J, et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother. 2007;60(1):100–6.

    Article  PubMed  CAS  Google Scholar 

  66. Sasaki J, Yamanouchi S, Kudo D, Endo T, Nomura R, Takuma K et al. Micafungin concentrations in the plasma and burn eschar of severely burned patients. Antimicrob Agents Chemother. 2011.

  67. Konishi H, Fukushima K, Saotome T, Hamamoto T, Eguchi Y, Sudo M, et al. Impact of plasma exchange on pharmacokinetic disposition of micafungin. Ther Apher Dial. 2010;14(3):358–63.

    Article  PubMed  CAS  Google Scholar 

  68. Gumbo T, Hiemenz J, Ma L, Keirns JJ, Buell DN, Drusano GL. Population pharmacokinetics of micafungin in adult patients. Diagn Microbiol Infect Dis. 2008;60(3):329–31.

    Article  PubMed  CAS  Google Scholar 

  69. • Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother. 2011;55(11):5107–12. Data shown that micafungin systemic plasma clearance increased with weight, suggesting an individualized dosing regimen was required for obese populations.

    Article  PubMed  CAS  Google Scholar 

  70. •• Pound MW, Townsend ML, Drew RH. Echinocandin pharmacodynamics: review and clinical implications. J Antimicrob Chemother. 2010;65(6):1108–18. A recent, comprehensive review on the pharmacodynamic properties of the echinocandins and their clinical relevance.

    Article  PubMed  CAS  Google Scholar 

  71. Andes D, Diekema DJ, Pfaller MA, Prince RA, Marchillo K, Ashbeck J, et al. In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(2):539–50.

    Article  PubMed  CAS  Google Scholar 

  72. Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J. In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(10):3497–503.

    Article  PubMed  CAS  Google Scholar 

  73. Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother. 2005;49(12):5058–68.

    Article  PubMed  CAS  Google Scholar 

  74. •• Andes D, Ambrose PG, Hammel JP, Van Wart SA, Iyer V, Reynolds DK, et al. Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob Agents Chemother. 2011;55(5):2113–21. Pharmacokinetic and pharmacodynamic findings of the study suggest that species-specific echinocandin susceptibility breakpoints are important to predict clinical efficacy.

    Article  PubMed  CAS  Google Scholar 

  75. •• Howard SJ, Livermore J, Sharp A, Goodwin J, Gregson L, Alastruey-Izquierdo A, et al. Pharmacodynamics of echinocandins against Candida glabrata: requirement for dosage escalation to achieve maximal antifungal activity in neutropenic hosts. Antimicrob Agents Chemother. 2011;55(10):4880–7. A recent pharmacodynamic study which demonstrates that currently recommended echinocandins dosing regimens are predicted to have fungistatic effects; higher doses are needed in neutropenic hosts.

    Article  PubMed  CAS  Google Scholar 

  76. Antachopoulos C, Meletiadis J, Sein T, Roilides E, Walsh TJ. Concentration-dependent effects of caspofungin on the metabolic activity of Aspergillus species. Antimicrob Agents Chemother. 2007;51(3):881–7.

    Article  PubMed  CAS  Google Scholar 

  77. Wiederhold NP, Kontoyiannis DP, Chi J, Prince RA, Tam VH, Lewis RE. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis. 2004;190(8):1464–71.

    Article  PubMed  CAS  Google Scholar 

  78. Ikawa K, Nomura K, Morikawa N, Ikeda K, Taniwaki M. Assessment of micafungin regimens by pharmacokinetic-pharmacodynamic analysis: a dosing strategy for Aspergillus infections. J Antimicrob Chemother. 2009;64(4):840–4.

    Article  PubMed  CAS  Google Scholar 

  79. Ernst EJ, Klepser ME, Pfaller MA. Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida albicans and Cryptococcus neoformans. Antimicrob Agents Chemother. 2000;44(4):1108–11.

    Article  PubMed  CAS  Google Scholar 

  80. Fleischhacker M, Radecke C, Schulz B, Ruhnke M. Paradoxical growth effects of the echinocandins caspofungin and micafungin, but not of anidulafungin, on clinical isolates of Candida albicans and C. dubliniensis. Eur J Clin Microbiol Infect Dis. 2008;27(2):127–31.

    Article  PubMed  CAS  Google Scholar 

  81. Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, et al. Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates. Antimicrob Agents Chemother. 2009;53(8):3347–52.

    Article  PubMed  CAS  Google Scholar 

  82. Chamilos G, Lewis RE, Albert N, Kontoyiannis DP. Paradoxical effect of Echinocandins across Candida species in vitro: evidence for echinocandin-specific and candida species-related differences. Antimicrob Agents Chemother. 2007;51(6):2257–9.

    Article  PubMed  CAS  Google Scholar 

  83. Fortwendel JR, Juvvadi PR, Perfect BZ, Rogg LE, Perfect JR, Steinbach WJ. Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin. Antimicrob Agents Chemother. 2010;54(4):1555–63.

    Article  PubMed  CAS  Google Scholar 

  84. • Miceli MH, Bernardo SM, Lee SA. In vitro analysis of the occurrence of a paradoxical effect with different echinocandins and Candida albicans biofilms. Int J Antimicrob Agents. 2009;34(5):500–2. In vitro findings confirmed that echinocandins are highly active against C. albicans biofilms and each echinocandin demonstrated different effects against the biofilms.

    Article  PubMed  CAS  Google Scholar 

  85. Shields RK, Nguyen MH, Du C, Press E, Cheng S, Clancy CJ. Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum. Antimicrob Agents Chemother. 2011;55(6):2641–7.

    Article  PubMed  CAS  Google Scholar 

  86. Kauffman CA, Carver PL. Update on echinocandin antifungals. Semin Respir Crit Care Med. 2008;29(2):211–9.

    Article  PubMed  Google Scholar 

  87. Sable CA, Nguyen BY, Chodakewitz JA, DiNubile MJ. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis. 2002;4(1):25–30.

    Article  PubMed  CAS  Google Scholar 

  88. Glasmacher A, Cornely OA, Orlopp K, Reuter S, Blaschke S, Eichel M, et al. Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients. J Antimicrob Chemother. 2006;57(1):127–34.

    Article  PubMed  CAS  Google Scholar 

  89. Marr KA, Hachem R, Papanicolaou G, Somani J, Arduino JM, Lipka CJ, et al. Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A. Transpl Infect Dis. 2004;6(3):110–6.

    Article  PubMed  CAS  Google Scholar 

  90. Sanz-Rodriguez C, Lopez-Duarte M, Jurado M, Lopez J, Arranz R, Cisneros JM, et al. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections. Bone Marrow Transplant. 2004;34(1):13–20.

    Article  PubMed  CAS  Google Scholar 

  91. Stone JA, Migoya EM, Hickey L, Winchell GA, Deutsch PJ, Ghosh K, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother. 2004;48(11):4306–14.

    Article  PubMed  CAS  Google Scholar 

  92. Dowell JA, Stogniew M, Krause D, Henkel T, Weston IE. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol. 2005;45(2):227–33.

    Article  PubMed  CAS  Google Scholar 

  93. • Cornely OA, Pappas PG, Young JA, Maddison P, Ullmann AJ. Accumulated safety data of micafungin in therapy and prophylaxis in fungal diseases. Expert Opin Drug Saf. 2011;10(2):171–83. A recent analysis of pooled databases from 17 clinical studies demonstrated favorable safety profile for micafungin.

    Article  PubMed  CAS  Google Scholar 

  94. Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, et al. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother. 2004;48(6):2021–4.

    Article  PubMed  CAS  Google Scholar 

  95. Vazquez JA, Schranz JA, Clark K, Goldstein BP, Reboli A, Fichtenbaum C. A phase 2, open-label study of the safety and efficacy of intravenous anidulafungin as a treatment for azole-refractory mucosal candidiasis. J Acquir Immune Defic Syndr. 2008;48(3):304–9.

    Article  PubMed  CAS  Google Scholar 

  96. • Ryan DM, Lupinacci RJ, Kartsonis NA. Efficacy and safety of caspofungin in obese patients. Med Mycol. 2011;49(7):748–54. A recent analysis of pooled clinical trial databases suggested that caspofungin was effective and well tolerated in treating obese patients with IA and candidiasis.

    PubMed  Google Scholar 

  97. van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–16.

    Article  PubMed  Google Scholar 

  98. Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, et al. Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation. Int J Hematol. 2008;88(5):588–95.

    Article  PubMed  CAS  Google Scholar 

  99. Chou LS, Lewis RE, Ippoliti C, Champlin RE, Kontoyiannis DP. Caspofungin as primary antifungal prophylaxis in stem cell transplant recipients. Pharmacotherapy. 2007;27(12):1644–50.

    Article  PubMed  CAS  Google Scholar 

  100. Mattiuzzi GN, Alvarado G, Giles FJ, Ostrosky-Zeichner L, Cortes J, O’Brien S, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother. 2006;50(1):143–7.

    Article  PubMed  CAS  Google Scholar 

  101. • Fortun J, Martin-Davila P, Montejo M, Munoz P, Cisneros JM, Ramos A, et al. Prophylaxis with caspofungin for invasive fungal infections in high-risk liver transplant recipients. Transplantation. 2009;87(3):424–35. A prospective, multicenter, open-label study suggested that caspofungin was efficacious and well-tolerated, as antifungal prophylactic agent in high-risk liver transplant recipients.

    Article  PubMed  CAS  Google Scholar 

  102. Senn L, Eggimann P, Ksontini R, Pascual A, Demartines N, Bille J, et al. Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients. Intensive Care Med. 2009;35(5):903–8.

    Article  PubMed  Google Scholar 

  103. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391–402.

    Article  PubMed  CAS  Google Scholar 

  104. Kubiak DW, Bryar JM, McDonnell AM, Delgado-Flores JO, Mui E, Baden LR, et al. Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis. Clin Ther. 2010;32(4):637–48.

    Article  PubMed  CAS  Google Scholar 

  105. de Wet NT, Bester AJ, Viljoen JJ, Filho F, Suleiman JM, Ticona E, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther. 2005;21(7):899–907.

    Article  PubMed  CAS  Google Scholar 

  106. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294–9.

    Article  PubMed  CAS  Google Scholar 

  107. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother. 2002;46(2):451–7.

    Article  PubMed  CAS  Google Scholar 

  108. Kuse E-R, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007;369(9572):1519–27.

    Article  PubMed  CAS  Google Scholar 

  109. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020–9.

    Article  PubMed  CAS  Google Scholar 

  110. Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24):2472–82.

    Article  PubMed  CAS  Google Scholar 

  111. Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, et al. A multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009;48(12):1676–84.

    Article  PubMed  CAS  Google Scholar 

  112. Pappas PG, Rotstein CMF, Betts RF, Nucci M, Talwar D, De Waele JJ, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007;45(7):883–93.

    Article  PubMed  CAS  Google Scholar 

  113. Gumbo T, Drusano GL, Liu W, Kulawy RW, Fregeau C, Hsu V, et al. Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia. Antimicrob Agents Chemother. 2007;51(3):968–74.

    Article  PubMed  CAS  Google Scholar 

  114. Dignan FL, Evans SO, Ethell ME, Shaw BE, Davies FE, Dearden CE, et al. An early CT-diagnosis-based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality. Bone Marrow Transplant. 2009;44(1):51–6.

    Article  PubMed  CAS  Google Scholar 

  115. • Herbrecht R, Maertens J, Baila L, Aoun M, Heinz W, Martino R, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant. 2010;45(7):1227–33. Pivotal clinical study demonstrated that caspofungin was effective and well tolerated as the first-line agent in treating allogeneic hematopoietic SCT patients with mycologically documented proven/probable invasive aspergillosis.

    Article  PubMed  CAS  Google Scholar 

  116. Viscoli C, Herbrecht R, Akan H, Baila L, Sonet A, Gallamini A, et al. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients. J Antimicrob Chemother. 2009;64(6):1274–81.

    Article  PubMed  CAS  Google Scholar 

  117. Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39(11):1563–71.

    Article  PubMed  CAS  Google Scholar 

  118. Hiemenz JW, Raad II, Maertens JA, Hachem RY, Saah AJ, Sable CA, et al. Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort. Eur J Clin Microbiol Infect Dis. 2010;29(11):1387–94.

    Article  PubMed  CAS  Google Scholar 

  119. Denning DW, Marr KA, Lau WM, Facklam DP, Ratanatharathorn V, Becker C, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect. 2006;53(5):337–49.

    Article  PubMed  Google Scholar 

  120. Caillot D, Thiebaut A, Herbrecht R, de Botton S, Pigneux A, Bernard F, et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer. 2007;110(12):2740–6.

    Article  PubMed  CAS  Google Scholar 

  121. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004;39(6):797–802.

    Article  PubMed  CAS  Google Scholar 

  122. Rieger CT, Ostermann H, Kolb HJ, Fiegl M, Huppmann S, Morgenstern N, et al. A clinical cohort trial of antifungal combination therapy: efficacy and toxicity in haematological cancer patients. Ann Hematol. 2008;87(11):915–22.

    Article  PubMed  CAS  Google Scholar 

  123. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, et al. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer. 2003;98(2):292–9.

    Article  PubMed  CAS  Google Scholar 

  124. Singh N, Limaye AP, Forrest G, Safdar N, Munoz P, Pursell K, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006;81(3):320–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Dr. S. Chen and Dr. M. Slavin has worked as a consultant for the Antifungal Advisory Board, Pfizer Australia, and the Antifungal Advisory Board, Merck; Dr. D.C.M Kong has received research grants from NHMRC, Gilead Sciences, CASS Foundation, PDL Ltd, Department of Health and Aging, Pharmacy Guild, and FRED and travel support from Pfizer; Dr. M. Slavin reported no potential conflicts of interest relevant to this article.

Author information

Authors and Affiliations

  1. Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Chin Fen Neoh & David C. M. Kong

  2. Department of Infectious Diseases, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, 3002, Australia

    Monica A. Slavin

  3. Centre for Infectious Diseases and Microbiology and The University of Sydney, Westmead Hospital, 3rd level, ICPMR Building, Darcy Road, Westmead, New South Wales, 2145, Australia

    Sharon C.-A. Chen

Authors
  1. Chin Fen Neoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David C. M. Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monica A. Slavin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sharon C.-A. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharon C.-A. Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neoh, C.F., Kong, D.C.M., Slavin, M.A. et al. Pharmacological and Host Considerations Surrounding Dose Selection and Duration of Therapy with Echinocandins. Curr Fungal Infect Rep 6, 95–106 (2012). https://doi.org/10.1007/s12281-012-0085-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-012-0085-y

Keywords

Search

Navigation